Within the last decade numerous investigators have reported that certain endogenous compounds inhibit neurotransmitter release via presynaptic receptors. In vitro studies have demonstrated that agonists which fall into four distinct classes of receptor activation (norepinephrine, acetylcholine, histamine, and dopamine) are capable of inhibiting the release of norepinephrine from adrenergic nerves. Data by the principal investigator demonstrate that a presynaptic mechanism to decrease stimulation-induced vasoconstriction exists in the in situ canine renal vasculature. Intrarenal modulation of this mechanism by prostaglandins and the renin angiotensin system has not been examined. Further, suggestive evidence for a cholinergic and/or dopaminergic feedback regulation of adrenergic nerve function, as opposed to a norepinephrine-induced negative feedback, has been presented. The proposed studies will provide definitive knowledge of this basic regulatory mechanism of renal adrenergic neurotransmission from which rational therapeutic approached to disease processes may proceed. In anesthetized dogs, renal vasoconstrictor responses to renal nerve stimulation and intra-arterial norepinephrine injections will be compared before and during infusions of histamine and specific H1 and H2 agonists. A decrease in the vasoconstrictor response to nerve stimulation relative to the vasoconstrictor response produced by exogenous norepinephrine is considered indicative of a decreased neuronal function resulting from infused agent. More importantly, the release of renal neuronal norepinephrine will be determined to substantiate a presynaptic effect of the drugs as opposed to a possible alteration of postsynaptic receptor sensitivity. Intrarenal modulation by prostaglandins and angiotensin on this mechanism will be evaluated by performing similar experiments after administration of indomethacin (prostaglandin synthetase inhibitor) and saralasin. The histamine receptor type will be characterized by using specific H1 and H2 receptor blocking agents (tripelennamine and cimetidine, respectively). Finally studies will be performed to determine whether drugs will modulate the release of renal catecholamines when the release is evoked by reflex sympathetic discharge (carotid artery occlusion and sciatic nerve stimulation).